Vedolizumab In Ulcerative Colitis Research Articles

P0595 Comparative effectiveness between ustekinumab and vedolizumab after anti-TNF failure in Ulcerative Colitis: Real-world experience

Abstract Background Ustekinumab (UST) and vedolizumab (VED) have proven to be effective therapies for ulcerative colitis (UC), with similar safety profiles. There are limited real-world studies comparing the effectiveness between UST and VED in UC, especially after anti-TNF failure1–4. Our aim was to evaluate the real-world efficacy and safety of UST and VED in UC patients previously exposed to anti-TNF therapies across multiple Canadian institutions. Methods This was a multicentre retrospective study looking at 12 months of clinical data for patients with UC who had previously been exposed to at least one anti-TNF. These patients were from McGill University Health Centre, Hamilton Health Sciences, and London Health Sciences Centre. The primary outcome was clinical remission at 6 months, defined by a partial Mayo score (pMS) ≤ 2, Mayo Endoscopic Score (MES) ≤ 1, or physician’s judgement of clinical remission. Secondary outcomes included clinical remission at 12 months, clinical response, biochemical remission and response, and drug persistence at 12 months. Clinical response was defined as a decrease in pMS ≥ 2 points or physician’s judgement of clinical response. Biochemical remission was defined as c-reactive protein (CRP) < 5mg/L and/or fecal calprotectin (FCP) < 250μg/g. Biochemical response was defined as a reduction of CRP or FCP by 50% from baseline. These parameters were all evaluated at 6 and 12 months. Adverse events were summarized for all patients after 12 months. Results One hundred and fifty patients were included: 28 in UST and 122 in VED. Mean age was 38.4 (SD 15.6) in UST and 43.8 (SD 16.8) in VED. Percentage of female patients was 67.9% in UST and 53.3% in VED. Mean baseline partial mayo score was 3.78 (SD 3.07) for UST and 4.48 (SD 2.43) for VED. Mean disease duration was 10.63 years (SD 8.44) for UST and 11.80 years (SD 8.25) for VED. There was no significant difference in clinical remission between UST or VED, for data that was available at each time point (UST 65.0% vs. VED 72.6%, p=0.49 at 6 months; UST 68.4% vs. VED 82.3%, p=0.17 at 12 months). There was no significant difference between UST and VED for biochemical remission at 6 and 12 months. Higher MES at baseline was negatively associated with clinical remission in UST and VED with univariate analysis, though only significant in VED when adjusted for sex, age, and disease duration (OR 0.07, 95% CI [0-0.26], p=0.0006). There was no significant difference between drug persistence at 12 months (95.0% UST vs. 91.5% VED, p=0.41). Infectious adverse events were similar between groups (17.9% UST vs. 4.1% VED, p=0.07), with no serious adverse events. Conclusion This real-world multicentre Canadian study shows similar efficacy and safety profiles for UST and VED in UC over 1 year.

P0755 Long-term safety of subcutaneous vedolizumab in Ulcerative Colitis and Crohn’s disease: Findings from the VISIBLE OLE study

Abstract Background Vedolizumab (VDZ) is a gut selective, monoclonal anti-α4β7 integrin antibody approved for the treatment of moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD) and is available in subcutaneous (SC) formulation. This analysis assessed the long-term safety outcomes of specific interest to the SC formulation of VDZ. Methods Patients (pts) who participated in VISIBLE 1 or VISIBLE 2 were eligible to enrol in VISIBLE OLE (NCT02620046). In VISIBLE 1, pts with UC were treated with placebo, VDZ SC or VDZ intravenous (IV). In VISIBLE 2, pts with CD were treated with placebo or VDZ SC. In VISIBLE OLE, pts received VDZ SC 108mg every 2 weeks (Q2W) or weekly. Pts received training on SC administration, and most injections were conducted at home by pt or caregiver. Safety of VDZ SC included assessing anti-VDZ antibody (AVA) status and injection site reaction (ISR) adverse events. Blood specimens for AVA assessment were collected 30 minutes before dosing every 16 weeks, at the final dose and the final safety visit 18 weeks after last dose. Data were assessed by treatment pts received during VISIBLE 1 and 2. Results Overall, 288 pts with UC and 458 pts with CD enrolled in VISIBLE OLE. A mean of 91.1 and 74.2 SC injections were completed by pts with UC and CD, respectively, during the OLE. Among pts with UC, the positive AVA rate was higher in pts previously treated with placebo (17.3%) than those treated with VDZ SC (3.4%) or IV (2.6%) (Table 1). The positive AVA rate was also higher among pts with CD previously treated with placebo (11.4%) than with VDZ SC (1.8%). A total of 14/288 pts (4.9%) with UC reported ISRs (Table 2), most of which were mild and none were serious. Two pts developed moderate ISRs; neither required dose modification and both were resolved. Overall, 19/458 pts (4.1%) with CD reported ISRs (Table 2). The majority of ISRs were mild, 2 were moderate and none were severe, and none required dose modification. No direct correlation between AVA status and ISRs was identified, with 11/14 pts (78.6%) with UC and 17/19 pts (89.5%) with CD who reported ISRs being AVA negative. All 5 pts who were AVA positive and reported an ISR had previously received placebo. The highest rate of ISRs were in pts who received placebo in VISIBLE 1 (13.5%). Conclusion No new long-term safety events were identified with the VDZ SC route of administration compared to IV, except for ISRs. A higher proportion of patients who had previously been treated with placebo than those treated with VDZ during VISIBLE 1 and 2 were AVA positive during VISIBLE OLE, supporting a benefit of continued therapy with VDZ SC after IV induction, rather than cessation of treatment for a period of time.

P1168 Real-world evidence comparison of the effectiveness of ustekinumab with anti-TNF or vedolizumab in ulcerative colitis: 2-year maintenance therapy results from the prospective, observational RUN-UC study

Abstract Background Observational real-world evidence (RWE) studies on the effectiveness of ustekinumab (UST) in ulcerative colitis (UC) are needed in addition to RCTs, which may not represent everyday clinical practice. For this reason, the prospective, controlled, propensity score (PS)-adjusted RUN-UC study was conducted on UC patients starting a new biologic therapy with a follow-up period of up to 3 years. The aim of the present analysis was to evaluate the effectiveness of 2-year maintenance therapy with UST vs. anti-TNF or vedolizumab (VDZ). Methods Between 2020-2022, 507 UC patients starting a new therapy with UST or other biologics were enrolled in 34 IBD-experienced centres in Germany. After the exclusion of patients with a stoma, small molecules and missing outcomes, the final sample consisted of 483 patients. Clinical remission (CR) (pMayo ≤ 1 plus a bleeding subscore=0) and steroid-free remission (CR and no systemic use of steroids or oral budesonide) were considered as outcomes. PS adjustment with inverse probability of treatment weighting (IPTW) was implemented to reduce confounders' effect. Results A total of 483 UC-patients [153 UST (bio-naïve: 13), 165 anti-TNF (ADA: 30.3%, IFX: 61.8%, GOL: 7.9%) (bio-naïve: 114) and 165 VDZ (bio-naïve: 106)] were included in the analysis. The PS-adjustment reduced systemic differences in the baseline parameters (UST/anti-TNF/VDZ: 43.1/46.1/50.9% males, 23.5/24.2/20.6% EIMs), in particular, the "bio-experienced" characteristic was also equalised, between the groups. Treatment persistence over 24 months showed differences between UST (68.6%), VDZ (73.3%) and anti-TNF (58.8%) (p=0.012), but this was only statistically significant for VDZ vs anti-TNF (p=0.005) but not for UST vs VDZ (p> 0.05) and UST vs anti-TNF (p>0.05) (Figure 1). The PS-weighted 24-month effectiveness (n=367) of UST (mITT analysis) in terms of clinical remission and steroid-free remission (Table 1) differed between the following groups (CR: UST 33.3%, anti-TNF 30.2%, VDZ 48.0%) compared to VDZ (p=0.031), but not compared to anti-TNF (UST vs anti-TNF p>0.05 and anti-TNF vs VDZ p=0.005). A sub-analysis evaluating steroid-free remission in bio-experienced patients after one prior anti-TNF treatment showed no statistical difference. was (UST 41.5%, anti-TNF 20.0% and VDZ 43.8%; p=0.130). Conclusion In this prospective RUN-UC study with PS-weighted groups, UST, anti-TNF and VDZ showed a more variable 24-month effectiveness, favouring VDZ over UST and anti-TNF. However, in a subgroup of bio-experienced patients with only one anti-TNF before baseline, steroid-free remission was numerically but not statistically higher with UST and VDZ than with anti-TNF.

P0957 Flow of Advanced Therapy Pathways and Variations over Time in Crohn’s Disease and Ulcerative Colitis: Data from the Persistence Australian National IBD Cohort (PANIC5)

Abstract Background Choice of advanced therapy (AT) in Crohn’s disease (CD) and ulcerative colitis (UC) have increased, however the optimal positioning and sequencing of agents are unknown. We present the first national data on sequencing for all AT treatments in Australia with Sankey diagrams. Methods We analysed the Persistence Australian National IBD Cohort (PANIC) 5 registry, including all UC and CD patients on AT via the Pharmaceutical Benefits Scheme up to December 2021. Sankey diagrams were created using Plotly, a Python-based tool. Each AT was coded as a node along the x-axis, and the y-axis represented patients’ treatment pathways, including sequential switches and stops from first to fifth-line treatments. Patients were divided into tertiles based on first AT commencement date (T1, T2, and T3) for both UC and CD data, and trends across these periods were compared. Statistical analyses were performed using SPSS. Results In a cohort of 9,671 UC patients (23,220 patient-years), 45% (n=539) discontinued first-line treatment in T1, which was 2.8 times more likely compared to 16% in T3 (p < 0.001). Additionally, 15% of patients in T1 transitioned to a second advanced therapy (AT), whereas 35% did so in T3 (p < 0.001). TOF was less frequently used in bio-naïve patients but more commonly prescribed in bio-exposed patients. Notably, in T3, TOF was the only therapy to show a significant increase in use from first- to fifth-line treatment, with the number of patients rising from 84 to 330, a 293% increase. In a cohort of 19,087 CD patients (79,677 patient-years), 48% (n=1465) discontinued first-line TNFi treatment in T1, making them 2.1 times more likely to stop treatment compared to T3 (p < 0.001). Due to limited treatment options in T1, only 20% of patients transitioned to second-line advanced therapy (AT), compared to 38% in T3. Furthermore, with the introduction of UST in T3, it was 2.1 times more likely to be prescribed to bio-exposed patients than ADA, the second most commonly used therapy in this group during T3. Conclusion This study underscores the increasing diversity of AT pathways for IBD patients, resulting in improved treatment retention over time. In both Crohn’s disease and ulcerative colitis, patients in T3 were less likely to discontinue treatment compared to those in T1, largely due to the expanded use of TOF and UST as salvage therapies. These findings provide important insights into the optimal sequencing of AT in IBD, demonstrating that a broader array of treatment options enhances patient adherence by offering more effective salvage strategies. References Ko Y, Paramsothy S, Yau Y, Leong RW. Superior treatment persistence with ustekinumab in Crohn’s disease and vedolizumab in ulcerative colitis compared with anti-TNF biological agents: real-world registry data from the Persistence Australian National IBD Cohort (PANIC) study. Aliment Pharmacol Ther. 2021 Aug;54(3):292-301. doi: 10.1111/apt.16436. Epub 2021 Jun 20. PMID: 34151447.

P0971 Effectiveness of Vedolizumab in Bio-Naïve Chinese Patients with Crohn’s Disease: A Subgroup Analysis of Second Interim Analysis of the VALUE Study

Abstract Background Vedolizumab (VDZ) is a humanized monoclonal antibody, that selectively targets α4β7 integrin and is approved for Crohn’s disease (CD) and Ulcerative colitis (UC). Previous studies demonstrated better efficacy of VDZ in bio-naïve pts with CD, however, there is lack of sufficient data in Chinese pts. VALUE study (NCT04872491) is a prospective, multicenter, single-armed observational study evaluating the safety and effectiveness of VDZ in UC and CD patients (pts). Methods This subgroup of bio-naïve pts with CD in second interim analysis of VALUE trial was assessed for clinical effectiveness (clinical response: ≥3 point-reduction in Harvey-Bradshaw index (HBI) score; clinical remission: HBI score ≤4; endoscopic remission: absence of any ulcers excluding aphthous ulcers.) on treatment of Vedolizumab, at week 14, 30, and 54. (Data cutoff: 21 Oct 23). Results Of the 91 pts with CD, 57 pts (62.64%) were bio-naïve, with a mean HBI score of 6.0±3.51 with the median duration of CD of 2.693 (4.1384) years. The majority of disease locations were Ileocolonic (49.12%) with 2 (3.51%) pts had history of Fistulas (Table 1). After treatment with VDZ, 44.44% (16/36), 52% (13/25) and 53.85% (7/13) achieved clinical response at week 14, 30 and 54, respectively. Overall, 83.33% (30/36), 96.15% (25/26) and 92.31% (12/13) pts achieved clinical remission at week 14, 30 and 54, respectively. Additionally, 100% of pts (13/13) achieved clinical response or remission, by 54 weeks (Figure 1). Further, 66.67% (4/6), 33.33% (2/6) and 0/1 pts achieved endoscopic remission at week 14 ,30 and 54, respectively. Conclusion This study demonstrated good effectiveness of VDZ in bio-naïve patients with CD in China.

P0799 Efficacy and Safety of Dual Therapy for Refractory Inflammatory Bowel Disease in a Danish Cohort

Abstract Background Patients with Crohn’s disease (CD) and ulcerative colitis (UC) may become refractory to monotherapy with biologics or small molecules. Dual therapy, combining biologics and small molecules, has been proposed for this challenging population. While awaiting randomized studies, real-world data on its efficacy and safety are crucial. This study contributes to the evidence on dual therapy in a Danish adult IBD cohort. Methods Medical records from May 2018 to May 2023 were reviewed for CD and UC patients undergoing dual therapy with biologics and/or small molecules in outpatient gastroenterology clinics at Aarhus University Hospital and Regional Hospital Randers. Patients treated for at least three months were included and followed until treatment discontinuation or the end of the study period. Patient characteristics, clinical outcomes, adverse events, and efficacy data were collected at baseline and follow-up. Results Seventy-four patients (47 with CD and 27 with UC) received a total of 79 dual therapies. The median duration of dual therapy was 488 days for CD and 412 days for UC. The most common combinations were adalimumab and ustekinumab in CD (46%) and adalimumab and vedolizumab in UC (35%). Clinical remission was achieved in 56% of CD patients and 62% of UC patients. Steroid-free follow-up was observed in 81% of CD patients and 52% of UC patients (Table 1). In CD, dual therapy significantly reduced stool frequency, bloody stools, calprotectin levels, and Harvey-Bradshaw Index (HBI) scores. In UC, stool frequency, nighttime stools, abdominal pain, CRP, calprotectin, and Simple Clinical Colitis Activity Index (SCCAI) scores significantly decreased, while hemoglobin and albumin levels significantly improved. Serious adverse events (SAEs) occurred in 12% of UC patients and 14% of CD patients, consistent with prior studies of adult and pediatric cohorts [1, 2]. No UC patients required colectomy during the study period. Conclusion This retrospective study demonstrates a substantial rate of clinical remission and acceptable safety in refractory IBD patients receiving dual therapy. The findings highlight prolonged treatment duration, significant clinical improvements, and a manageable SAE profile. Dual therapy represents a promising approach for refractory and complex IBD, though the risk of SAEs must always be balanced against therapeutic benefits.

P0694 Clinical response trajectories identify distinct subpopulations of ulcerative colitis patients and are linked to disease outcome across different therapy classes. Patient level analysis of 2378 participants from 6 randomized controlled trials in moderate-severe UC representing 8 different mechanisms of action.

Abstract Background In randomized placebo-controlled trials (RCTs) for ulcerative colitis (UC), remission rates below 40% (wk52). Landmark analyses using independent endpoints provide approvable estimands for overall efficacy but overlook individual variability.Notably, a subset of patients achieves deeper remission levels. Post hoc analysis of the SELECTION trial (filgotinib) demonstrated that treating daily PRO2 scores (stool frequency, rectal bleeding) as time-series data reveals discrete subpopulations.Patients with in the faster response trajectory groups achieve wk52 endpoints at higher rates including disease control. Methods In a cross-industry/academic collaboration, data from 2,378 UC responders from RCTs of adalimumab, brepocitinib, etrasimod, etrolizumab, ozanimod, ritlecitinib, ustekinumab, and vedolizumab in UC were analyzed for PRO2-based treatment response trajectories using Group-based trajectory modeling (GBTM). Using random-effects logistic regression, trajectory groups were linked to wk 12 and 52 outcomes, including comprehensive disease control (CDC), defined as achieving remission in endoscopy, symptoms, lab markers, and histology. Meta-analyses of baseline demographics/disease characteristics examined predictors of trajectory group affiliation and CDC at wk 52. Results GBTM identified 3–5 distinct response trajectories for each mechanism of action (MOA), ranging from super-fast responses to slow and incomplete responses or relapse, based on PRO2 dynamics. Meta-analysis revealed baseline factors associated with faster response, including prior biologic failure, lower endoscopic activity (Mayo-ES 2 vs. 3), lower Robarts Histology Index, lower baseline disease activity and male sex (0.78 [0.66, 0.93]) (Fig1). Across therapies, remission, mucosal healing, and comprehensive disease control (CDC) were most frequently achieved in fast and super-fast responders (15–37%), compared to slow or non-responders (2.6–8.1%). Random-effects logistic regression confirmed better clinical outcomes for faster responders (Tab1). Conclusion Distinct subgroups (response trajectories) with specific PRO2-based response dynamics were consistently identified. In all trials, patients with (super)fast responses had significantly higher odds of achieving mucosal healing, deep remission, and comprehensive disease control (CDC) at wk52. While some baseline characteristics were linked to faster responses, they only partially account for the observed separation of patient groups. Response trajectories likely reflect underlying heterogeneity in disease biology in the interaction with the different MOA (i.e. endotypes). RNASeq analysis of transcriptome regulation in these patients aims to further explore this hypothesis. References Schreiber S et al. UEG Journal, doi:10.1002/ueg2.12686

Factors affecting 1-year persistence with vedolizumab for ulcerative colitis: a multicenter, retrospective real-world study.

The objectives of this real-world study were to determine 1-year persistence with vedolizumab in patients with ulcerative colitis and to evaluate factors contributing to loss of response. In this multicenter, retrospective, observational chart review, patients with moderately to severely active ulcerative colitis who received ≥ 1 dose of vedolizumab in clinical practice at 16 tertiary hospitals in Japan (from December 2018 through February 2020) were enrolled. Persistence with vedolizumab was 64.5% (n = 370); the median follow-up time was 53.2 weeks. Discontinuation due to loss of response among initial clinical remitters was reported in 12.5% (35/281) of patients. Multivariate analysis showed that concomitant use of tacrolimus (odds ratio [OR], 2.76; 95% confidence interval [CI], 1.00-7.62; P= 0.050) and shorter disease duration (OR for median duration ≥ 7.8 years vs. < 7.8 years, 0.33; 95% CI, 0.13-0.82; P= 0.017) were associated with discontinuation due to loss of response. Loss of response was not associated with prior use of anti-tumor necrosis factor alpha therapy, age at the time of treatment, disease severity, or concomitant corticosteroids or immunomodulators. Of the 25 patients with disease duration < 1 year, 32.0% discontinued due to loss of response. Persistence with vedolizumab was consistent with previous reports. Use of tacrolimus and shorter disease duration were the main predictors of decreased persistence.

Precision medicine: Externally validated explainable AI support tool for predicting sustainability of infliximab and vedolizumab in ulcerative colitis

Drug sustainability (DS), a surrogate marker for drug efficacy, is important, especially when aiming for precision medicine. However, it lacks reliable prediction methods. To develop and externally validate a web-based artificial intelligence(AI)-derived tool for predicting DS of infliximab and vedolizumab in patients with moderate-to-severe Ulcerative Colitis (UC). Data from three Israeli centers included infliximab or vedolizumab patients treated for >54 weeks. Sustainability meant no corticosteroids, hospitalizations or surgeries. Machine learning techniques predicted >54-week and overall DS using baseline clinical data. The model was developed using data from 246 patients from Rabin Medical Center and externally validated on 67 patients from Rambam Health Care Campus and Sheba Medical Center. No significant difference in DS was observed across the datasets. Most patients were biologic-naïve and primarily treated with vedolizumab. The model performed well, with an area under the ROC curve of 0.86, and showed good accuracy (65.5 %-76.9 %) across the test sets. The study introduces a novel, AI-based tool for predicting >54-week DS of infliximab and vedolizumab in moderate-to-severe UC, using baseline parameters. This can aid clinical decision-making in the framework of precision medicine, promising to optimize disease management while maintaining physician autonomy.

Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial

Background and aimsThe impact of thiopurine de-escalation whilst on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab. MethodsThis multi-centre randomized controlled trial recruited UC patients on vedolizumab 300mg IV every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore[MES]≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score≥3 and fecal calprotectin>150μg/g or increase in MES≥1 from baseline), fecal calprotectin remission (<150μg/g), C-reactive protein remission (<5mg/L), centrally-read endoscopic remission (MES=0), histologic remission (Nancy index=0), histo-endoscopic remission and adverse events. ResultsIn total, 62 patients were randomized to continue (n=20) or withdraw (n=42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7μg/mL [IQR:12.3-18.5μg/mL] versus 15.9μg/mL [IQR:10.1-22.7μg/mL] respectively, P=0.36). The continue group had significantly higher fecal calprotectin remission (95.0% [19/20] versus 71.4% [30/42], P=0.03), histologic remission (80.0% [16/20] versus 48.6% [18/37], P=0.02) and histo-endoscopic remission (75.0% [15/20] versus 32.4% [12/37], P=0.002) than the withdrawal group. Histological activity (HR:15.5 [95%CI:1.6-146.5],P=0.02) and prior anti-TNF exposure (HR:6.5 [95%CI:1.3-33.8],P=0.03) predicted clinical relapse after thiopurine withdrawal. ConclusionThiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic and histo-endoscopic activity. Histological activity and prior anti-TNF exposure may predict disease relapse upon thiopurine withdrawal for patients using vedolizumab for UC; Australian and New Zealand Trial Registry, number ACTRN12618000812291.

Confocal laser endomicroscopy as predictive biomarker of clinical and endoscopic efficacy of vedolizumab in ulcerative colitis: The DETECT study.

In patients with ulcerative colitis (UC), no biomarker is available to help the physician to choose the most suitable biotherapy. The primary objective of this pilot study was to assess the feasibility of identification of α4β7- and TNF-expressing cells, to predict the response to vedolizumab using confocal laser endoscopy (CLE). Patients with moderate-to-severe UC, naïve of biotherapy, received vedolizumab. Clinical evaluation was performed at each infusion. Endoscopic evaluation was performed before inclusion and at week 22. Fresh colonic biopsies were stained using FITC-labelled vedolizumab and Alexa fluor-labelled adalimumab and ex vivo dual-band CLE images were acquired. Blood samples were collected to measure trough concentrations of vedolizumab and to determine absolute counts of T and B cells subpopulations, NK cells and monocytes. Nineteen patients were enrolled in the study and received at least one dose of vedolizumab. Clinical remission and endoscopic improvement were observed in 58% of whom 5 patients (45%) had an endoscopic subscore of 0. In terms of clinical response and remission, endoscopic improvement and histologic response, FITC-conjugated vedolizumab staining tended to be higher in responder patients compared to non-responders at week 22. A threshold value of 6 positive FITC-vedolizumab staining areas detected by CLE seemed informative to discriminate the responders and non-responders. The results were similar in terms of clinical remission and endoscopic improvement with a sensitivity of 78% and a specificity of 85% (p = 0.05). Trough concentrations and blood immune cells were not associated with responses to vedolizumab. This pilot study demonstrate that dual-band CLE is feasible to detect α4β7- and TNF-expressing cells. Positive α4β7 staining seems to be associated with clinical and endoscopic remission in UC patients treated by anti-α4β7-integrin, subject to validation by larger-scale studies. Clinical-trial.gov: NCT02878083.

REAL-WORLD SAFETY AND EFFICACY OF USTEKINUMAB AND VEDOLIZUMAB IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Abstract CONTEXT/PURPOSE Ustekinumab and vedolizumab are approved biologicals to treat adults with inflammatory bowel disease (IBD) but currently administered off-label for children. Aims: (1) assess safety and adverse events during treatment with ustekinumab or vedolizumab in pediatric IBD and (2) assess steroid free clinical remission and mucosal healing at 6 months and 1 year. METHODS Retrospective chart review of pediatric patients (&amp;lt;22 years) with IBD treated at an academic hospital and two affiliated practices. Inclusion: Patients with IBD who received either ustekinumab or vedolizumab between January 2015 to June 2022 with minimum of 6 months follow up. Clinical remission assessed by Pediatric Ulcerative Colitis Activity Index (PUCAI) &amp;lt; 10 and short Pediatric Crohn’s Disease Activity Index (shPCDAI) &amp;lt;15, and mucosal healing by fecal calprotectin &amp;lt;250 mcg/gram. RESULTS Fifty-eight patients received vedolizumab and 55 patients received ustekinumab. Patients with ulcerative colitis (UC) or IBD unclassified (IBDU) on vedolizumab were more likely to be in remission at 6 months (58% vs. 42%, p = 0.3, Table 1) and significantly higher at achieving 1-year steroid free remission (64% vs. 27%, p = 0.019) compared to ustekinumab. Over two thirds of biologic naïve and about half of biologic exposed patients who received vedolizumab achieved 1-year steroid free remission (78% vs. 58%, Figure 1). All patients who received ustekinumab were biologic exposed. In Crohn’s disease (CD), no significant difference was seen in children receiving vedolizumab compared to ustekinumab at 6 months remission (57% vs. 63%, p = 0.7) or 1-year steroid free remission (70% vs. 70%, p &amp;gt;0.9). All biologic naïve patients and half of biologic exposed patients who received vedolizumab achieved 1 year steroid free remission. Both bionaive and two thirds of biologic exposed patients who received ustekinumab achieved 1-year steroid free remission (100% vs. 67%). When comparing vedolizumab and ustekinumab, no significant difference was observed in 6 month remission (73% vs. 59%, p = 0.2) and 1-year steroid free remission based on calprotectin (61% vs. 66%, p = 0.7). Similar to clinical remission rates, biologic naïve patients tended to have higher remission rates based on calprotectin. Five patients each had minor adverse events with ustekinumab and vedolizumab, and 20 were hospitalized mostly for IBD flare. CONCLUSION Both biologicals were safe and effective in achieving clinical remission at 6 months and 1 year. They were more effective when used in bionaive patients, although numbers were very low for ustekinumab. The superior efficacy of vedolizumab in UC and IBDU at 1-year may be attributed to larger cohort of bionaive patients. Larger multicenter prospective studies are needed to validate these findings regarding efficacy and safety of vedolizumab and ustekinumab in pediatric IBD. Table 1 Remission on Vedolizumab and Ustekinumab Figure 1 Remission on Vedolizumab vs. Ustekinumab Stratified by Biologic Exposure

OP40 Transcriptomic signature of response to vedolizumab in patients with moderate-to-severe ulcerative colitis: Results from an international, multicentre, retrospective cohort study

Abstract Background Transcriptomic analysis has the potential to facilitate drug development and clinical decision making in inflammatory bowel disease. Current understanding of pharmacodynamic response to vedolizumab is limited by a lack of publicly available mucosal biopsy RNA samples/sequencing data and corresponding clinical information. We aimed to identify gene signatures associated with response to vedolizumab in ulcerative colitis (UC) patients by pooling data from 3 international sites. Methods Patients receiving vedolizumab for the treatment of moderate-to-severe UC at Hospital Clínic de Barcelona (IDIBAPS), Mount Sinai Hospital (MSH), and University of California, San Diego (UCSD) with baseline and post-treatment (week 14 [± 4 weeks]) mucosal biopsy RNA-sequencing data and Mayo Clinic endoscopic subscores (MCES) were eligible for inclusion. Endoscopic response was defined as an MCES &amp;lt;1. Demographic and clinical data were collected. Differential expressed genes (DEGs) between baseline and week 14 were identified using linear mixed models with a &amp;gt;1.5 or &amp;lt;-1.5-fold change (adjusted P-value &amp;lt;.05). Enrichment was performed using Reactome pathway analysis and a previously published UC gene signature (adjusted P-value &amp;lt;.05).1 Analyses were performed using R version 4.3.0. Results Twenty-three patients were included (IDIBAPS: n=12; MSH: n=8; UCSD: n=3). Site-specific differences in sex, surgical history, and corticosteroid use were observed (Table). Analysing data by site yielded a relatively small number of DEGs between baseline and week 14 (IDIBAPS=57 [27 up-regulated, 30 down-regulated]; MSH=0; UCSD=0) among endoscopic responders (IDIBAPS: n=5; MSH: n=7; UCSD: n=2). Combining data from the 3 sites increased the number of DEGs among endoscopic responders at week 14 (n=14) to 1162 (662 up-regulated and 500 down-regulated). The down-regulated DEGs were enriched for genes involved in 37 of 103 up-regulated Reactome pathways in UC, including neutrophil degranulation, interleukin-4 and interleukin-13 signalling, interleukin-10 signalling, and integrin cell surface interactions. The up-regulated DEGs were enriched for genes involved in 1 of 39 down-regulated Reactome pathways in UC (Drug ADME). Conclusion We defined a pharmacodynamic signature using mucosal biopsies from UC patients who had endoscopic response to vedolizumab at week 14. The signature was enriched for several, but not all, pathways involved in UC. In addition to providing insight into vedolizumab’s mechanism of action, we underscored the utility of multi-site collaboration to access data, increase statistical power, and enhance the generalizability of research findings. Reference: 1. Linggi et al. Sci Rep 2021;11:18243.

P108 Response to vedolizumab in ulcerative colitis is associated with reduced neutrophil extracellular traps formation and IL-1β production: insights from NEUTROVED study

Abstract Background Vedolizumab (VDZ) is a humanized mAb against integrin α4β7. VDZ inhibits gut inflammation by impeding intestinal T-cell homing, however, recent data suggest that effects of α4β7 blocking extend beyond T-cells to alterations in innate immunity. Neutrophils are key components of innate immune response and inflammation in ulcerative colitis (UC). Studies have provided evidence linking neutrophils with UC pathogenesis, through autophagy induction and production of IL-1β-enriched neutrophil extracellular traps (NETs). NEUTROVED aimed to investigate the effects of VDZ treatment on neutrophils that may be associated with clinical and endoscopic response. Methods Patients with moderate-to-severe UC who received VDZ in standard medical care were evaluated in two timepoints, 24 hours before treatment initiation (T1) and at week 14 of treatment (T2). Clinical/endoscopic scores and common laboratory indexes were evaluated. In parallel, RNA-sequencing in peripheral neutrophils was performed, and markers of NETs in plasma and intestinal biopsies were assessed. Results In total 5 patients completed the study until today (Table 1). In T2, 4 patients demonstrated complete remission, and one patient had mild disease. No adverse events were recorded. RNA-sequencing analysis of paired samples revealed 248 significantly downregulated and 109 upregulated genes in peripheral neutrophils after VDZ treatment. Bioinformatics analysis using the GeneCodis4 web-based tool revealed that downregulated DEGs clustered mainly in immune-related pathways, including neutrophil degranulation, Toll-like receptor cascades, signaling by interleukins, NETs formation, and HIF-1 signaling pathway, while upregulated DEGs were involved in RNA metabolism-related processes, and the ribosome biogenesis pathway. A comparative analysis between these differentially expressed genes (DEGs) and our previous RNA-sequencing data of peripheral neutrophils isolated from active UC patients (n=24) highlighted a set of 168 DEGs as restored targets after VDZ therapy. Of note, several unique genes implicated in neutrophil activation, including IL-1 signaling components, were found significantly downregulated after VDZ therapy. In line with the abovementioned transcriptome alterations, markers of NETs and IL1β-bearing NETs in plasma and colonic tissue were significantly reduced, recapitalizing clinical and endoscopic response to VDZ. Conclusion Response to VDZ treatment in UC is related to anti-inflammatory actions on neutrophils characterized by reduced NETosis and IL-1β production through NETs. Further mechanistic studies investigating the possible effects of VDZ on innate immunity and neutrophil-mediated responses are warranted.

P792 Real-world evidence comparison of the effectiveness of ustekinumab with anti-TNF or vedolizumab in ulcerative colitis: 1-year maintenance therapy results from the prospective, observational RUN-UC study

Abstract Background Observational real-world evidence (RWE) studies on the effectiveness of ustekinumab (UST) in ulcerative colitis (UC) are needed in addition to RCTs, which may not represent everyday clinical practice. For this reason, the prospective, controlled, propensity score (PS)-adjusted RUN-UC study was conducted on UC patients starting a new biologic therapy with a follow-up period of up to 3 years. The aim of the present analysis was to evaluate the 1-year maintenance therapy effectiveness of UST vs. anti-TNF or vedolizumab (VDZ). Methods Between 2020-2022, 507 UC patients starting a new therapy with UST or other biologics were enrolled in 34 IBD-experienced centres in Germany. After the exclusion of patients with a stoma, small molecules and missing outcomes, the final sample consisted of 476 patients. Response modified (reduction in partial Mayo score (pMayo) by ≥3 points from baseline to month 12 and a reduction of at least 30% or achievement of remission at month 12), clinical remission (CR) (pMayo ≤ 1 plus a bleeding subscore=0) and steroid-free remission (pMayo ≤ 1, bleeding subscore=0 and no systemic use of steroids or oral budesonide use in the previous 8 weeks) were considered as outcomes. To reduce the effect of confounders, PS adjustment with inverse probability of treatment weighting (IPTW) was implemented. Health-related QoL was assessed by using the visual analogue scale (EQ-VAS) of the EQ-5D. Results A total of 476 UC-patients [147 UST (bio-naïve: 12), 168 anti-TNF (ADA: 32.7%, IFX: 59.5%, GOL: 7.7%) (bio-naïve: 114) and 161 VDZ (bio-naïve: 105)] were included in the analysis. The PS-adjustment eliminated systemic differences in the baseline parameters (UST/anti-TNF/VEDO: 42.2/47.0/50.3% males, 25.2/25.0/19.9% EIMs), in particular, the "bio-experienced" characteristic was also equalised, between the groups. Treatment persistence over 12 months was different between UST (93.9%), VDZ (87.0%) and anti-TNF (75.0%) (Fig. 1). The PS-weighted effectiveness of UST (mITT analysis) in terms of response, clinical and steroid-free remission at month 12 (Tab. 1) was comparable to that of anti-TNF and VDZ, as was also the case without PS-weighting (CR: UST 33.1%, anti-TNF 38.5%, VDZ 38.1%). Patients of all treatment groups showed significant improvements in QoL measured as the EQ-VAS after 12 months of treatment. Conclusion In this prospective RUN-UC study with PS-weighted groups, UST showed similar maintenance effectiveness compared to established biologics in UC (anti-TNF and VDZ) with a relatively higher treatment persistence of UST, probably serving as a proxy for effectiveness, suggesting that additional criteria, such as safety and patients´ profile, may play an important role in the selection of biologics.

Early Versus Late Use of Vedolizumab in Ulcerative Colitis: Clinical, Endoscopic, and Histological Outcomes.

We explored the potential for differential efficacy of vedolizumab between early and late ulcerative colitis [UC] with evaluation of clinical, endoscopic, and histological endpoints. This was a multicentre, multinational, open-label study in patients with moderately-to-severely active UC, defining early UC by a disease duration <4 years and bio-naïve and late UC by a disease duration > 4 years and additional exposure to tumour necrosis factor antagonists. Patients received standard treatment with intravenous vedolizumab for 52 weeks [300 mg Weeks 0, 2, 6, every 8 weeks thereafter without escalation]. The primary endpoint was corticosteroid-free clinical remission with endoscopic improvement [total Mayo score ≤2 with no subscore >1] at both Weeks 26 and 52. A total of 121 patients were included: in the "early" group, 25/59 [42.4%] achieved the primary endpoint versus 19/62 [30.6%] in the "late" group [p = 0.18]. There were no significant differences between the two groups in endoscopic improvement [Week 26: "early" 32/59 [54.2%] versus "late" 29/62 [46.8%]; p = 0.412; Week 52: 27/59 [45.8%] versus 25/62 [40.3%]; p = 0.546] or in histological remission [Robarts Histopathology Index <3 without neutrophils in the epithelium and lamina propria] [Week 26: 24/59 [40.7%] versus 21/62 [33.9%]; p = 0.439; Week 52: 22/59 [37.3%] versus 22/62 [35.5%]; p = 0.837]. No significant differences in clinical, endoscopic, and histological outcomes were observed between "early" and "late" disease.

Acute tubulointerstitial nephritis possibly caused by vedolizumab for ulcerative colitis in a kidney transplant recipient: A case report.

Vedolizumab, which is used to effectively treat ulcerative colitis (UC), is a humanized monoclonal antibody that specifically inhibits α4β7 integrin on lymphocytes and prevents lymphocyte migration into the intestinal tissues. Herein, we report a case of acute tubulointerstitial nephritis (ATIN) probably caused by vedolizumab in a kidney transplant recipient (KR) with UC. Approximately 4 years after kidney transplantation, the patient developed UC and was treated initially with mesalazine. Treatment continued with the addition of infliximab later; however, he was hospitalized because of poor symptom control and treated with vedolizumab. His graft function declined rapidly after vedolizumab was administered. Allograft biopsy revealed ATIN. Since no evidence of graft rejection was found, vedolizumab-associated ATIN was diagnosed. The patient was treated with steroids, and his graft function improved. Unfortunately, he finally underwent total colectomy considering that UC was refractory to medical treatment. Previously, cases of vedolizumab-induced acute interstitial nephritis have been reported; however, none were associated with KRs. This is the first report of ATIN in KR which was possibly induced by vedolizumab.

Mucosal α4β7+ Lymphocytes and MAdCAM+ Venules Predict Response to Vedolizumab in Ulcerative Colitis.

Therapeutic strategies for patients with ulcerative colitis (UC) are based on patient- and disease-related factors in combination with drug characteristics but fail to predict success in individual patients. A considerable proportion of UC patients do not respond to the biological vedolizumab. Therefore, pretreatment biomarkers for therapeutic efficacy are urgently needed. Mucosal markers related to the integrin-dependent T lymphocyte homing could be potent predictors. We prospectively included 21 biological- and steroid-naive UC patients with moderate-to-severe disease activity planned to escalate therapy to vedolizumab. At week 0, before initiating treatment, colonic biopsy specimens were obtained for immunophenotyping and immunohistochemistry. Clinical and endoscopic disease activity were determined at week 16 after 4 infusions of vedolizumab. In addition, we retrospectively included 5 UC patients who were first treated with anti-tumor necrosis factor α before receiving vedolizumab to compare with biological-naive patients. Abundance of α4β7 on more than 8% of all CD3+ T lymphocytes in colonic biopsies at baseline was predictive for responsiveness to vedolizumab (sensitivity 100%, specificity 100%). The threshold for the proportion of MAdCAM-1+ and PNAd+ of all venules in the biopsies predictive for responsiveness to vedolizumab was ≥2.59% (sensitivity 89%, specificity 100%) and ≥2.41% (sensitivity 61%, specificity 50%), respectively. At week 16, a significant decrease of α4β7+CD3+T lymphocytes was demonstrated in responders (18% [12%-24%] to 8% [3%-9%]; P = .002), while no difference was seen in nonresponders (4% [3%-6%] to 3%; P = .59). UC responders to vedolizumab have a higher percentage of α4β7+CD3+ T lymphocytes and a higher proportion of MAdCAM-1+ venules in colonic biopsies than nonresponders before initiating therapy. Both analyses could be promising predictive biomarkers for therapeutic response and may lead to more patient tailored treatment in the future.

Practical Primer Addressing Real-World Use Scenarios of Subcutaneous Vedolizumab in Ulcerative Colitis and Crohn's Disease: Post Hoc Analyses of VISIBLE Studies.

Vedolizumab, an anti-α4β7 integrin approved for intravenous (IV) treatment of moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD), was evaluated as a subcutaneous (SC) formulation in maintenance therapy for UC and CD in phase 3 VISIBLE 1, 2, and open-label extension studies, and recently approved in Europe, Australia, and Canada. Our aim was to evaluate efficacy and safety of IV and SC vedolizumab in clinically relevant UC and CD scenarios. Post hoc data analyses from VISIBLE trials examined: (1) whether baseline characteristics predict clinical response to 2 vs 3 IV vedolizumab induction doses; (2) efficacy and safety of switching during maintenance vedolizumab IV to SC in patients with UC; (3) vedolizumab SC after treatment interruption of 1-46 weeks; (4) increasing dose frequency of vedolizumab SC from every 2 weeks (Q2W) to every week (QW) after disease worsening. No baseline characteristics were identified as strong predictors of response to 2 vs 3 vedolizumab infusions. Most patients achieved clinical response after 2 or 3 doses of IV vedolizumab maintained with SC treatment. Clinical remission and response rates were maintained in patients transitioned from maintenance vedolizumab IV to SC treatment. Of patients with UC, ≥75% achieved response following resumption after dose interruption. Escalation to QW dosing resulted in ≥45% of patients regaining response after loss while receiving vedolizumab Q2W. Clinical real-world scenarios with vedolizumab SC were reviewed using VISIBLE studies data. Vedolizumab SC provides an additional dosing option for patients with UC and CD.

Explore the influence of vitamin D supplementation on clinical efficacy and drug retention rate of vedolizumab in patients with ulcerative colitis

Objectives: To analyze the influence of vitamin D supplementation on clinical efficacy and drug retention rate of vedolizumab (VDZ) in patients with ulcerative colitis (UC). Methods: Retrospective study. By retrieving the clinical database of the Second Affiliated Hospital of Wenzhou Medical University, the patients with moderately to severely active UC were collected, who underwent VDZ treatment from January 2020 to June 2022. The modified Mayo score and Mayo endoscopic score (MES) were employed to evaluate disease activity and intestinal inflammation in UC patients, respectively. According to whether vitamin D was supplemented during VDZ treatment, the patients were divided into supplementary group and non-supplementary group. According to baseline serum 25(OH) D level, UC patients were divided into vitamin D deficiency group and non-deficiency group. According to whether vitamin D was supplemented, the patients of each group were divided into supplementary subgroup and non-supplementary subgroup, respectively. The clinical response rate, clinical remission rate and mucosal healing rate at week 30 after receiving VDZ treatment and the retention rate of VDZ at the 72nd week were observed. The effect of baseline serum 25 (OH) D level on the efficacy of vitamin D supplementation was analyzed by chi-square test. The effects of vitamin D supplementation on the clinical efficacy and drug retention of VDZ in UC were analyzed by chi-square test and Kaplan-Meier curve, respectively. Results: A total of 80 patients with moderately to severely active UC, who were aged (39.4±13.0) years(18-75 years), 37 male and 43 female, were included. There were 43 cases in supplementary group and 37 cases in non-supplementary group. There were 59 cases in the deficiency group, including 32 cases in the supplementary subgroup and 27 cases in the non-supplementary subgroup. There were 21 cases in the non-deficiency group, including 11 cases in the supplementary subgroup and 10 cases in the non-supplementary subgroup. At week 30, the average level of serum 25(OH) D was shown to be higher in supplementary group than that at week 0 [(24.5±5.4) vs (17.7±6.7) μg/L, P<0.001]. At week 30, in contrast with non-supplementary group, erythrocyte sedimentation rate(ESR)[75.0% (24.3%, 86.7%) vs 32.7% (-2.6%, 59.3%), P=0.005] and modified Mayo score [(4.7±2.8) vs (2.3±2.7) points, P<0.001] and MES score [(1.2±1.1) vs (0.4±0.9) points, P=0.001] were significantly reduced, clinical response rate [79.1%(34/43) vs 56.8%(21/37), P=0.032], clinical remission rate [67.4%(29/43) vs 29.7%(11/37), P=0.001] and mucosal healing rate [72.1%(31/43) vs 37.8%(14/37), P=0.002] were higher. At week 72, drug retention rate of VDZ was shown to be higher in supplementary group than in non-supplementary group [55.8%(24/43) vs 27.0%(10/37), P=0.004]. The further analysis showed that vitamin D supplementation could only improve clinical response rate[71.9%(23/32) vs 44.4%(12/27), P=0.033], clinical remission rate[62.5%(20/32) vs 14.8%(4/27), P<0.001], mucosal healing rate[68.8%(22/32) vs 22.2%(6/27), P<0.001] and drug retention rate [53.1%(17/32) vs 13.8%(4/27), P=0.001] in the patients with vitamin D deficiency. Conclusion: Vitamin D supplementation contributes to improving clinical response rate, clinical remission rate, mucosal healing rate and drug retention rate of VDZ in UC patients.